N-pyridyl carboxamides and derivatives

ABSTRACT

A compound selected from those of formula (I):   &lt;IMAGE&gt; (I)  where m is equal to 0 or 1 and Het, A, X, R,R1, R2, R3, R4 and the ring &lt;IMAGE&gt;  are defined in the description, and a medicinal product comprising the same for treating an inflammatory disorder.

The present application is a division of our prior-filed applicationSer. No. 08/450,346, filed May 25, 1995, now U.S. Pat. No. 5,712,294.

The present invention relates to novel N-pyridyl carboxamides andderivatives, to processes for their preparation and to thepharmaceutical compositions which contain them.

N-Pyridyl carboxamide structures are already described. Thus, patentapplication WO 9304580 describes N-(4-pyridyl)arylacetamides aspesticides.

The Applicant has now discovered that novel N-pyridyl carboxamidederivatives were non-toxic derivatives endowed with high-levelanti-inflammatory and/or diuretic properties. The anti-inflammatoryactivity of the derivatives of the invention has the particularlyadvantageous feature of manifesting itself after systemicadministration, but also after topical administration, which, besidesthe standard indications of anti-inflammatory agents, renders thecompounds of the invention particularly valuable in skin diseases suchas psoriasis. In addition, the diuretic component of certain products ofthe invention makes them very valuable in certain renal inflammatorydiseases.

The invention more specifically relates to the derivatives of formula(I): ##STR3## in which m is equal to 0 or 1,

the symbol ##STR4## representing the pyridine ring when m is equal to 0and pyridine N-oxide when m is equal to 1, the pyridine system ##STR5##being to the group ##STR6## which bears it either in the 2-position orin the 3-position of pyridine; R₁ and R₂, which may be identical ordifferent, are chosen, independently of each other, from hydrogen,amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, nitro andhalogen,

R₃ and R₄, which may be identical or different, are chosen,independently of each other, from amino, alkylamino, dialkylamino,alkyl, hydroxy, alkoxy, nitro and halogen,

R represents a hydrogen atom or an alkyl group,

A represents a single bond; and in this case Het represents a groupchosen from pyrazine, substituted pyrazine, benzothiophene, substitutedbenzothiophene, 4-oxo 4H!benzopyran, substituted 4-oxo 4H!benzopyran,pyrrole, substituted pyrrole, pyrroline, substituted pyrroline,pyrrolidine, substituted pyrrolidine, piperidine, substitutedpiperidine, pyridine, substituted pyridine, benzopyran, benzopyransubstituted with one or more alkyl groups, chromane, chromanesubstituted with one or more alkyl groups, 3-carboxy-5-alkylisoxazole,3-alkoxycarbonyl-5-alkylisoxazole, phthalimido and substitutedphthalimido,

or alternatively A represents an alkylene group which is unsubstitutedor substituted with one or more alkyl groups, or an alkenylene groupwhich is unsubstituted or substituted with one or more alkyl groups; andin this case Het represents a group chosen from thiophene, substitutedthiophene, pyrazine, substituted pyrazine, benzothiophene, substitutedbenzothiophene, 4-oxo 4H!benzopyran, substituted 4-oxo 4H!benzopyran,pyrrole, substituted pyrrole, pyrroline, substituted pyrroline,pyrrolidine, substituted pyrrolidine, piperidine, substitutedpiperidine, pyridine, substituted pyridine, benzopyran, benzopyransubstituted with one or more alkyl groups, chromane, chromanesubstituted with one or more alkyl groups, 3-carboxy-5-alkylisoxazole,3-alkoxycarbonyl-5-alkylisoxazole, phthalimido and substitutedphthalimido,

X represents an oxygen atom, a sulfur atom, an imino group or an iminogroup substituted with a group chosen from alkyl, alkoxy, hydroxy,amino, arylalkyloxy and aryloxy,

the enantiomers and diastereoisomers thereof and the addition saltsthereof with a pharmaceutically acceptable acid or base,

it being understood that, except where otherwise mentioned:

the term "substituted" relating to the thiophene, pyrazine,benzothiophene, 4-oxo- 4H!benzopyran, pyrrole, pyrroline, pyrrolidine,piperidine, pyridine and phthalimido systems means that these systemsare substituted with one or more groups chosen from alkyl, alkoxy,trifluoromethyl, hydroxy, halogen, thiol and alkylthio,

the terms "alkyl", "alkoxy" and "alkylene", denote linear or branchedgroups containing from 1 to 6 carbon atoms,

the term "aryl" denotes a phenyl or naphthyl radical,

the term "alkenylene" denotes a linear or branched unsaturated chaincontaining from 2 to 6 carbon atoms.

Among the pharmaceutically acceptable acids which may be added to thecompounds of formula (I) in order to form a salt, there may bementioned, without any limitation, hydrochloric acid, sulfuric acid,tartaric acid, maleic acid, fumaric acid, oxalic acid, methanesulfonicacid and camphoric acid.

Among the pharmaceutically acceptable bases which may be used in orderto salify the compounds of the invention, non-exhaustive examples whichmay be mentioned are sodium hydroxide, potassium hydroxide,triethylamine, diethylamine, ethanolamine or diethanolamine, arginineand lysine.

The invention relates particularly to the compounds of formula (I) inwhich, taken together or separately,

the symbol ##STR7## represents a 2-pyridyl group, the symbol ##STR8##represents a 3-pyridyl group, two of the substituents R₁, R₂, R₃ and R₄represent a methyl radical,

R represents a hydrogen

X represents a sulfur,

X represents an imino group,

X represents an imino group substituted with a hydroxyl group, a methoxygroup, a methyl group or an amino group,

A represents a methylene,

Het represents a thiophene or substituted thiophene group,

Het represents a pyrazine or substituted pyrazine group,

Het represents a benzothiophene or substituted benzothiophene group,

Het represents a 4-oxo 4H!benzopyran or substituted 4-oxo 4H!benzopyrangroup,

Het represents a pyrrole or substituted pyrrole group,

Het represents a pyrrolidine or substituted pyrrolidine group,

Het represents a pyridine or substituted pyridine group,

Het represents a phthalimido or substituted phthalimido group,

Het represents a 3-carboxy-5-methylisoxazole group,

and Het represents a 3-ethoxycarbonyl-5-methylisoxazole group.

Particular cases of the invention relate, for example, to:

the compounds having the formula (IA): ##STR9## in which m represents 0or 1, and either Het represents the thiophene group and A represents amethylene,

or Het represents the pyrazine group or the pyrazine group substitutedwith an alkyl group and A is a single bond,

and X represents an oxygen atom, a sulfur atom, an imino group or animino group substitued with a hydroxyl group, a methoxy group, a methylgroup, an amino group or a benzyloxy group,

the enantiomers and diastereoisomers thereof and the addition saltsthereof with a pharmaceutically acceptable acid,

the compound which is N-(4,6-dimethyl-2-pyridyl)-2-thienylacetamide, theN-oxide thereof and the addition salts thereof with a pharmaceuticallyacceptable acid,

the compound which is N-(4,6-dimethyl-2-pyridyl)-3-thienylacetamide, theN-oxide thereof and the addition salts thereof with a pharmaceuticallyacceptable acid,

the compound which isN-(4,6-dimethyl-2-pyridyl)-2-pyrazinylcarbamidoxime of formula ##STR10##the N-oxide thereof and the addition salts thereof with apharmaceutically acceptable acid,

the compound which isN-(4,6-dimethyl-2-pyridyl)-O-methyl(2-pyrazinyl)carbamidoxime of formula##STR11## the N-oxide thereof and the addition salts thereof with apharmaceutically acceptable acid,

the compound which isN-(4,6-dimethyl-2-pyridyl)(5-methyl-2-pyrazinyl)thiocarboxamide, theN-oxide thereof and the addition salts thereof with a pharmaceuticallyacceptable acid,

the compound which isN-(4,6-dimethyl-2-pyridyl)(2-pyrazinyl)carboxamidine, the N-oxidethereof and the addition salts thereof with a pharmaceuticallyacceptable acid,

the compound which isN-(4,6-dimethyl-2-pyridyl)-N'-methyl-2-pyrazinylcarboxamidine ##STR12##the N-oxide thereof and the addition salts thereof with apharmaceutically acceptable acid.

The subject of the present invention is also the process for thepreparation of the compounds of formula (I), wherein a compound offormula (1): ##STR13## where R, R₁, R₂, R₃, R₄ and the ring ##STR14##have the same definition as in formula (I), is used as starting materialwhich derivative is either condensed with a derivative of formula (2):

    Het--A--COOH                                               (2)

where Het and A have the same definition as in the formula (I), to givea derivative of formula (I/a): ##STR15## where Het, A, R, R₁, R₂, R₃, etR₄ and the ring ##STR16## have the same definition as above, whichderivative of formula (I/a) is subjected to a thionating agent to give aderivative of formula (I/b): ##STR17## where Het, A, R, R₁, R₂, R₃ et R₄and the ring ##STR18## have the same meaning as above, which derivativeof formula (I/b) is condensed with a derivative of formula (3):

    NH.sub.2 --Z                                               (3)

where Z represents a hydrogen atom or a hydroxyl, alkyl, alkoxy, amino,arylalkyloxy or aryloxy group, to give a derivative of formula (I/c):##STR19## where Het, A, R, R₁, R₂, R₃, R₄, Z and the ring ##STR20## havethe same definition as above, or which derivative is reacted with acompound of formula (4): ##STR21## where r is an alkyl group, in orderto obtain compounds of formula (5): ##STR22## in which r, R, R₁, R₂, R₃,and R₄ are as defined above,

which compounds are reacted with a compound of formula Het-H where Hetis as defined in formula (I),

in order to obtain compounds of formula (I/d), ##STR23## in which Het,r, R, R₁, R₂, R₃, and R₄ are as defined above,

which compounds of formula (I/d) may, if so desired, be reduced by theaction of sodium borohydride, for example, to give compounds of formula(I/e): ##STR24## in which Het, r, R, R₁, R₂, R₃, and R₄ are as definedabove,

or alternatively which compounds, in the case where Het represents apyrrolidine group, may react with alkyl chlorooximidoacetate of formula(6): ##STR25## where r' is an alkyl group, to give compounds of formula(1/f): ##STR26## in which r, r', R, R₁, R₂, R₃, and R₄ are as definedabove,

which compounds of formula (I/f) may, if so desired, be reacted withlithium hydroxide, in order to obtain compounds of formula (I/g):##STR27## in which r, R, R₁, R₂, R₃, and R₄ are as defined above,

which derivatives of formula (I/a), (I/b), (I/c), (I/d), (I/e), (I/f)and (I/g) may, if so desired, be converted into pyridine N-oxides by theaction of aqueous hydrogen peroxide solution,

the derivatives of formula (I/a), (I/b), (I/c), (I/d), (I/e), (I/f) and(I/g) and the N-oxides thereof forming the set of derivatives of formula(I), the enantiomers and diastereoisomers of which derivatives offormula (I) may be separated and may be salified with a pharmaceuticallyacceptable acid or base.

The compounds of formula (I) possess advantageous pharmacologicalproperties.

Study of these properties has, indeed, shown that the derivatives offormula (I) were not toxic and were endowed with anti-inflammatoryactivity, which manifests itself both topically and systemically, aswell as diuretic activity.

This spectrum of activity thus makes the compounds of the presentinvention useful in the treatment of chronic or acute arthritis anduseful in a certain number of indications such as inflammatoryrheumatism, rheumatoid polyarthritis, rheumatoid spondylitis, arthrosis,articular rheumastism and lumbago. On account of their topical activity,the compounds of the invention are useful in the treatment of certainskin disorders such as psoriasis and eczema. In addition, on account oftheir diuretic activity, the compounds of the invention are useful inthe treatment of renal inflammatory diseases, nephritis,glomerulonephritis and pyelonephritis.

Another subject of the present invention is the pharmaceuticalcompositions containing a compound of formula (I), or one of theaddition salts thereof with a pharmaceutically acceptable acid or base,in combination with one or more pharmacologically acceptable excipients.

Among the pharmaceutical compositions according to the invention, theremay more particualrly be mentioned, as examples and in a non-limitingmanner, those which are suitable for oral, parenteral, nasal, rectal,perlingual, ocular, cutaneous, transcutaneous, percutaneous or pulmonaryadministration and especially injectable preparations, aerosols, eyedrops or nasal drops, suppositories, plain, film-coated or sugar-coatedtablets, gelatin capsules, wafer capsules, creams, ointments and dermalgels.

The appropriate dosage varies depending on the age, sex and weight ofthe patient, the route of administration, the nature of the complaintand treatments which are possibly associated therewith, and rangesbetween 1 mg and 5 grams per 24 hours, preferably between 1 mg and 100mg per 24 h, more particularly between 1 and 10 mg per 24 h, for example10 mg.

The examples which follow illustrate the invention and do not limit itin any way.

The infrared spectra are run as the potassium bromide pastillecontaining about 1% of the product to be analyzed.

The starting materials used are either commercially available or areaccessible to those skilled in the art from the literature and from thepreparations which do not form part of the invention but which areuseful for preparing some products of the invention.

PREPARATION: 5-BROMO-2,3-DIAMINO 4,6-DIMETHYLPYRIDINE

STAGE A: 2-AMINO-5-BROMO-4,6-DIMETHYLPYRIDINE

6.1 g (50 mmol) of 2-amino-4,6-dimethylpyridine are dissolved in 50 mlof acetic acid. A solution of 8 g (50 mmol) of bromine in 50 ml ofacetic acid is added dropwise using a dropping funnel. The reactionmedium is allowed to return to room temperature and the stirring iscontinued for 3 hours. The mixture is cooled in an ice bath and 40%sodium hydroxide is then added until the pH is basic. The mixture isfiltered and dried. The residue is taken up in a little isopropyl etherand then chromatographed on silica gel, eluting with this same solvent.The expected product is collected in the form of white crystals. It isrecrystallized from absolute ethanol.

Yield: 69%

STAGE B: 2-AMINO-5-BROMO-4,6-DIMETHYL-3-NITROPYRIDINE

4 g (20 mmol) of the product obtained in Stage A are dissolved in 16 mlof concentrated sulfuric acid with stirring and cooling in ice. Thesolution is brought to 55° C. and 1.3 ml of concentrated nitric acid areadded dropwise, care being taken to maintain the temperature between 55°and 60° C. The stirring is continued for 20 minutes and the mixture isthen poured onto crushed ice. The product is precipitated by addition of40% sodium hydroxide. It is filtered off, washed with water and thendried. 3.7 g of product are thus collected. The product isrecrystallized from 95° C. ethanol.

Yield: 75%

Melting point: 169° C.

STAGE C: 5-BROMO-2,3-DIAMINO-4,6-DIMETHYLPYRIDINE

A solution of 4.1 g (21.6 mmol) of SnCl₂ in 20 ml of concentrated HCl iscooled in an ice bath. 1.32 g (5.4 mmol) of product obtained in Stage Bare added gradually. The mixture is heated at 80° C. for 30 minutes. Itis allowed to cool and then poured onto crushed ice. The resultingmixture is basified by addition of sodium hydroxide. The precipitateformed is filtered off, washed with water and then dried. 1.06 g ofwhite powder are thus collected. The product is recrystallized fromtoluene.

Yield: 90%

Melting point: 183° C.

EXAMPLE 1 N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE

9.22 g of triphenylphosphine, 6.93 ml of trichlorobromomethane, 5 g of2-thienylacetic acid and 8.50 g of 2-amino-4,6-dimethylpyridine aredissolved in 120 ml of tetrahydrofuran. The mixture is brought to refluxand filtered, and the filtrate is concentrated; the residue ischromatographed on silica gel, eluting with dichloromethane, and theproduct obtained is recrystallized from isopropyl ether.

Yield: 78%

Melting point: 124°-125 C.

Elemental composition Calculated: C 63.33H 5.68N 11.36 Found: C 63.26H5.69N 11.34

Spectral characteristics

Infrared:3265 cm⁻¹ ν NH

Nuclear Magnetic Resonance (solvent CDCl₃)

Pyridine ring:

4-CH₃ : 2.29 ppm singlet

6-CH₃ : 2.36 ppm singlet

H₃ : 7.88 ppm singlet

H₅ : 6.72 ppm singlet

CH₂ --CO: 3.91 ppm singlet

EXAMPLE 2 N-ETHYL-N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE

3.4 g of 2-chloro-1-methylpyridinium iodide are dissolved in methylenechloride, followed by addition of:

1.89 g of 2-thienylacetic acid

2 g of 2-ethylamino-4,6-dimethylpyridine

4.6 ml of triethylamine

The mixture is brought to reflux. When the reaction is complete, themixture is filtered and evaporated to dryness; the residue is extracted;the organic phases are combined and dried. The solvent is evaporated offand the residue is chromatographed in a dichloromethane/ethanol mixture.An oily product is obtained.

Yield: 88%

Refractive index: 1,561

Spectral characteristics:

Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ --CH₃ --: triplet, CH₃, 3H, δ 1:1.12 ppm

CH₂ --CH₃ : quartet, CH₂, 2H, δ:3.80 ppm

EXAMPLE 3 N-HEXYL-N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE

The process is performed as in Example 2, but replacing the2-ethylamino-4,6-dimethylpyridine by 2-hexylamino-4,6-dimethylpyridine.The title product is obtained.

Yield: 60%

Refractive index: 1,547

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₃ --CH₂ : triplet 3H:0.83 ppm

CH₃ --CH₂ --CH₂ --CH₂ --CH₂ CH₂ --N: multiplet 6H: 1.26 ppm

CH₃ --CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --CH₂ --N: multiplet 2H: 1.51 ppm

CH₂ --: triplet 2H: 3.78 ppm.

EXAMPLE 4 N-(5-BROMO-4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE

By performing the process as in Example 2, but replacing the2-ethylamino -4,6-dimethylpyridine by2-amino-5-bromo-4,6-dimethylpyridine obtained in Stage A of thepreparation, the title product is obtained.

Recrystallization solvent: acetone

Yield: 86%

Melting point: 192° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ : singlet, 2H: 3.94 ppm

EXAMPLE 5 N-(3,5-DIBROMO-4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE

By performing the process as in Example 2, but replacing the2-ethylamino-4,6-dimethylpyridine by2-amino-3,5-dibromo-4,6-dimethylpyridine, the title product is obtained.

Melting point: 154° C.

EXAMPLE 6 N-(3,5-DICHLORO-2-PYRIDYL)-2-THIENYLACETAMIDE

By performing the process as in Example 1, but replacing the2-amino-4,6-dimethylpyridine by 2-amino-3,5-dichloropyridine, the titleproduct is obtained.

Recrystallization: isopropyl ether

Yield: 33%

Melting point:144°-145° C.

Spectral characteristics:

Infrared

3240 cm⁻¹, ν NH

1680 cm⁻¹, ν CO

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ : singlet 2H: 4.17 ppm

EXAMPLE 7 N-(2-AMINO-5-BROMO-4,6-DIMETHYL-3-PYRIDYL)-2-THIENYL ACETAMIDE

By performing the process as in Example 1, but replacing the2-amino-4,6-dimethylpyridine by 5-bromo-2,3-diamino-4,6-dimethylpyridine(preparation), the title product is obtained.

Recrystallization solvent: acetone

Yield: 49%

Melting point: 202° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ : singlet 2H; 4.01 ppm

EXAMPLE 8 N-(4,6-DIMETHYL-2-PYRIDYL)-5-BROMO-2-THIENYLACETAMIDE

By performing the process as in Example 1, but replacing the2-thienylacetic acid by 2-(5-bromo)thienylacetic acid, the title productis obtained.

Melting point: 87 ° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₂ : singlet 2H: 3.83 ppm

EXAMPLE 9 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 1, but replacing the2-thienylacetic acid by 3-thienylacetic acid, the title product isobtained.

Recrystallization: isopropyl ether

Yield: 65%

Melting point: 123°-124° C.

Spectral characteristics:

Infrared

1660 cm⁻¹ : ν CO

¹ H Nuclear Magnetic Resonance (CDCl₃) CH₂ --CO singlet 2H; 3.74 ppm.

EXAMPLE 10 N-(5-BROMO-4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 4, but replacing the2-thienylacetic acid by 3-thienylacetic acid, the title product isobtained.

Recrystallization: acetone

Yield: 55%

Melting point: 211° C.

Spectral characteristics:

Infrared

1650 cm⁻¹ : ν CO

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₂ CO singlet 2H; 3.76 ppm.

EXAMPLE 11 N-(5-BROMO-2-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 9, but replacing the 2-amino4,6-dimethylpyridine by 2-amino-5-bromopyridine, the title product isobtained.

Recrystallization solvent: isopropyl ether

Yield: 50%

Melting point: 117° C.

Spectral characteristics:

Infrared

1665 cm⁻¹ ; ν CO

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ : singlet 2H; 3.72 ppm

EXAMPLE 12 N-(3,5-DICHLORO-2-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 9, but replacing the2-amino-4,6-dimethylpyridine by 2-amino-3,5-dichloropyridine, the titleproduct is obtained.

Recrystallization: isopropyl ether

Yield: 30%

Melting point: 159°-160° C.

Spectral characteristics:

Infrared

1680 cm⁻¹ : ν CO

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ : singlet; 2H; 3.97 ppm.

EXAMPLE 13 N-(3,5 DIBROMO-4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 9, but replacing the2-amino-4,6-dimethylpyridine by2-amino-3,5-dibromo-4,6-dimethylpyridine, the title product is obtained.

Melting point: 157° C.

EXAMPLE 14 N-(4,6-DIMETHYL-2-PYRIDYL)-2-BROMO-3-THIENYLACETAMIDE

By performing the process as in Example 1, but replacing the5-bromo-2-thienylacetic acid by 2-bromo-3-thienylacetic acid, the titleproduct is obtained.

Melting point: 72° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₂ : singlet; 2H; 3.70 ppm.

EXAMPLE 15 N-(4,6-DIMETHYL-2-PYRIDYL)-2,5-DIBROMO-3-THIENYLACETAMIDE

By performing the process as in Example 1, but replacing the2-thienylacetic acid by 2,5-dibromo-3-thienylacetic acid, the titleproduct is obtained.

Melting point: 109° C.

Spectral characteristics:

1H Nuclear Magnetic Resonance (CDCl₃)

CH₂ : singlet; 2H; 3.64 ppm

EXAMPLE 16 N-ETHYL-N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 2, but replacing the2-thienylacetic acid by 3-thienylacetic acid, the oily title product isobtained.

Yield: 75%

Refractive index: 1,571

Spectral characteristics:

Infrared

1650 cm⁻¹ ν CO

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₃ --CH₂ : triplet 3H; δ: 1.12 ppm

CH₃ --CH₂ : quartet 2H; δ: 3.33 ppm

CH₂ --CO: singlet 2H; δ 3.55 ppm

EXAMPLE 17 N-(2-AMINO-5-BROMO-4,6-DIMETHYL-3-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 7, but replacing the2-thienylacetic acid by 3-thienylacetic acid, the title product isobtained.

Recrystallization: acetone

Yield: 50%

Melting point: 194° C.

Spectral characteristics:

Infrared

1635 cm⁻¹ ν CO

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ : singlet 2H; 3.84 ppm.

EXAMPLE 18 N-HEXYL-N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDE

By performing the process as in Example 3, but replacing the2-thienylacetic acid by 3-thienylacetic acid, the title product isobtained.

EXAMPLE 19 N-(4,6-DIMETHYL-2-PYRIDYL)-2-CHLORO-3-BENZOb!THIENYLACETAMIDE

By performing the process as in Example 1, but replacing the2-thienylacetic acid by 2-chloro-3-benzo b!thienylacetic acid, the titleproduct is obtained.

Recrystallization: isopropyl ether

Yield: 55%

Melting point: 123°.124° C.

Spectral characteristics:

Infrared

1660 cm⁻¹ ν CO

¹ H Nuclear Magnetic Resonance

CH₂ : singlet; 2H; 3.91 ppm

4-CH₃ : singlet; 3H; 2.22 ppm

6-CH₃ : singlet; 3H; 3.30 ppm.

EXAMPLE 20 N-(4,6-DIMETHYL-2-PYRIDYL)-4-OXO4H!BENZOPYRAN-2-YL-CARBOXAMIDE ##STR28##

By performing the process as in Example 1, but replacing the2-thienylacetic acid by 4-oxo 4H!benzopyran-2-ylcarboxylic acid, thetitle product is obtained.

Recrystallization: isopropyl ether

Yield: 60%

Melting point: 195° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

H.sub.β' : singlet 1H; 6.85 ppm

H.sub.β : singlet 1H; 8.02 ppm

EXAMPLE 21 N-(4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINECARBOXAMIDE

3 g of 2-pyrazinecarboxylic acid are dissolved in 20 ml of thionylchloride. The reactants are left in contact for 30 minutes at about 60°C. The excess thionyl chloride is evaporated off and the acid chlorideobtained is washed several times.

This acid chloride thus obtained is taken up in 20 ml of dichloroethane.In parallel, 3 g of 2-amino-4,6-dimethylpyridine are dissolved in 30 mlof dichloroethane. 3 ml of triethylamine are added, followed by the acidchloride solution prepared above. The reactants are left in contact for60 minutes. The residue is filtered off and then evaporated. The productis chromatographed on a column of silica eluting with dichloromethane.

Recrystallization: isopropyl ether

Yield: 75%

Melting point: 123°-125° C.

Spectral characteristics:

Infrared

1690 cm⁻¹ : ν CO

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₃ (4): singlet 3H; 2.37 ppm

CH₃ (6): singlet 3H; 2.46 ppm.

EXAMPLE 22 N-(5-BROMO-4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINECARBOXAMIDE

By performing the process as in Example 4, but replacing the2-thienylacetic acid by 2-pyrazinecarboxylic acid, the title product isobtained.

Recrystallization: acetone

Yield: 60%

Melting point: 206° C.

Spectral characteristics:

Infrared

1680 cm⁻¹ : ν CO

¹ H Nuclear Magnetic Resonance (CDCl₃)

H(pyridine): singlet; 8.17 ppm

H₆ (pyrazine): resolved doublet: 1H; 8.62 ppm

H₅ (pyrazine): doublet: 1H; 8.83 ppm, J5.6; 2.40 Hz

EXAMPLE 23 N-(3,5-DIBROMO-4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINE CARBOXAMIDE

By performing the process as in Example 5, but replacing the2-thienylacetic acid by 2-pyrazinecarboxylic acid, the title compound isobtained.

Melting point: 166° C.

EXAMPLE 24 N-(4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINETHIOCARBOXAMIDE

2.5 g of product obtained in Example 21 and 5.31 g of Lawesson's reagentare dissolved in 50 ml of toluene, and the solutions maintained atreflux for 4 h. It is filtered and the solvent is evaporated off. Theproduct is purified by chromatography on silica gel, eluting withdichloromethane.

The product is collected and recrystallized from isopropyl ether.

Yield: 45%

Melting point: 123° C.

Spectral characteristics:

Infrared

1665 cm⁻¹ : ν C=S

1H Nuclear Magnetic Resonance (solvent DMSO-d₆)

CH₃ (4): singlet 3H; 2.43 ppm

CH₃ (6): singlet 3H; 2.52 ppm

EXAMPLE 25 N-(4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINECARBOXAMIDE HYDRAZONE##STR29##

To 1 g of compound of Example 24 dissolved in 30 ml of ethanol is added0.6 ml of hydrazine monohydrate and the mixture is left stirring for 30minutes at room temperature. The reaction medium is then poured intoice-water. It is stirred vigorously for 20 minutes. The mixture isfiltered and dried and the residue is recrystallized from isopropylether.

Yield: 73%

Melting point: 156° C.

Spectral characteristics:

Infrared

3350 cm⁻¹ ν NH

1H Nuclear Magnetic Resonance (CDCl₃)

CH₃ (4): singlet 3H; 2.25 ppm

CH₃ (6): singlet 3H; 2.40 ppm

EXAMPLE 26 N-(4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINECARBAMIDOXIME ##STR30##

1.65 g of derivative obtained in Example 24 and 45 ml of ethanol areintroduced into a round-bottomed flask. The derivative is dissolvedunder hot conditions, and 2.34 g of hydroxylamine hydrochloride areadded, followed by 1.79 g of sodium carbonate dissolved in 20 ml ofwater. The mixture is maintained at reflux for 30 minutes. The reactionmedium is diluted in water, filtered and dried. The product is collectedand recrystallized from a methanol/chloroform mixture.

Yield: 80%

Melting point: 191° C.

Spectral characteristics:

Infrared

3270 cm⁻¹ ν (HN)

2500-2900 cm⁻¹ ν (OH)

¹ H Nuclear Magnetic Resonance ¹ H (DMSO-d₆)

CH₃ (4): singlet 3H; 1.80 ppm

CH₃ (6): singlet 3H; 2.17 ppm

EXAMPLE 27 N-(4,6-DIMETHYL-2-PYRIDYL)-O-METHYL-2-PYRAZINECARBAMIDOXIME##STR31##

By performing the process as in Example 26 but replacing thehydroxylamine hydrochloride by methoxylamine hydrochloride, the titleproduct is obtained.

Recrystallization: methanol

Yield: 88%

Melting point: 133° C.

Spectral characteristics:

Infrared

1610-1560 cm⁻¹ : ν CN

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₃ (4): singlet 3H; 2.10 ppm

CH₃ (6): singlet 3H; 2.15 ppm

OCH₃ : singlet 3H; 4.02 ppm

EXAMPLE 28 N-(4,6-DIMETHYL-2-PYRIDYL)-O-BENZYL-2-PYRAZINECARBAMIDOXIME##STR32##

By performing the process as in Example 26, but replacing thehydroxylamine hydrochloride by benzyloxylamine hydrochloride, the titleproduct is obtained.

Melting point: 84° C.

EXAMPLE 29 N-(4,6-DIMETHYL-2-PYRIDYL)-N'-METHYL-2-PYRAZINE CARBOXAMIDINE##STR33##

1.23 g of derivative obtained in Example 24 and 1.95 g of aqueous 40%methylamine solution are added to a round-bottomed flask containingethanol. The mixture is left to stir at room temperature, then filteredand evaporated. The oil obtained is crystallized from diethyl ether andrecrystallized from isopropyl ether.

Yield: 64%

Melting point: 103°-104° C.

Spectral characteristics:

Infrared

1625, 1610 cm⁻¹

¹ H Nuclear Magnetic Resonance (solvent DMSO-d₆)

CH₃ (4): singlet 3H; 2.03 ppm

CH₃ (6): singlet 3H; 2.18 ppm

N--CH₃ : singlet 3H; 2.91 ppm

EXAMPLE 30 N-(4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINECARBOXAMIDINE ##STR34##

1.2 g (4.91 mmol) of product obtained in Example 24 and 40 ml of ethanolare introduced into a two-necked round-bottomed flask. A stream ofammonia gas is bubbled through. The insoluble material is filtered offand the solvent is then evaporated off. The residue is recrystallizedfrom isopropyl ether.

Yield: 95%

Melting point: 148° C.

Spectral characteristics:

Infrared

ν CN 1625, 1600 cm⁻¹

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₃ (4) singlet 3H: 2.31 ppm

CH₃ (6) singlet 3H: 2.49 ppm

EXAMPLE 31N-(2-AMINO-5-BROMO-4,6-DIMETHYL-3-PYRIDYL)-2-PYRAZINECARBOXAMIDE##STR35##

By performing the process as in Example 7, but replacing the2-thienylacetic acid by 2-pyrazinecarboxylic acid, the title product isobtained.

Yield: 52%

Melting point: 224° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₃ (4): singlet(3H); 2.35 ppm

CH₃ (6): singlet (3H); 2.56 ppm

EXAMPLE 32 N-(4,6-DIMETHYL-2-PYRIDYL)-2-PYRAZINECARBOXAMIDE N-OXIDE##STR36##

A solution of 10 ml of glacial acetic acid and 0.7 ml of aqueoushydrogen peroxide solution (35%) are added, with stirring, to 1 g ofcompound obtained in Example 21. The reaction medium is heated at 70° C.for 7 h and then concentrated under reduced pressure and at lowtemperature.

The residual solution is cooled. The white solid obtained is filteredoff. It is washed with ice-water, dried and purified by chromatographyon silica gel. The residue is recrystallized from a methylenechloride/isopropyl ether mixture.

Yield: 66%

Melting point: 210° C.

Spectral characteristics:

Infrared

1225 cm⁻¹ : ν NO

¹ H Nuclear Magnetic Resonance (CDCl₃)

H₆ : resolved doublet, 1H, H₆

EXAMPLE 33 N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE N-OXIDE

By performing the process as in Example 32, but replacing theN-(4,6-dimethyl-2-pyridyl)-2-pyrazinecarboxamide (obtained in Example21) by N-(4,6-dimethyl-2-pyridyl)-2-thienylacetamide (obtained inExample 1), the title product is obtained.

Melting point: 154°-155° C.

EXAMPLE 34 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDE N-OXIDE

By performing the process as in Example 32, but using the compoundobtained in Example 9, the title product is obtained.

Melting point: 154° C.

EXAMPLES 35 TO 41

By performing the process as in Examples 24 to 30 but starting withN-(4,6-dimethyl-2-pyridyl)-2-thienylacetamide, the following arerespectively obtained.

EXAMPLE 35 N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLTHIOACETAMIDE

Melting point: 64° C.

EXAMPLE 36 N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE HYDRAZONE##STR37## EXAMPLE 37 N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDOXIME##STR38## EXAMPLE 38N-(4,6-DIMETHYL-2-PYRIDYL)-O-METHYL-2-THIENYLACETAMIDOXIME ##STR39##EXAMPLE 39 N-(4,6-DIMETHYL-2-PYRIDYL)-O-BENZYL-2-THIENYLACETAMIDOXIME##STR40##

Melting point: 87° C.

EXAMPLE 40 N-(4,6-DIMETHYL-2-PYRIDYL)-N'-METHYL-2-THIENYLACETAMIDINE##STR41## EXAMPLE 41 N-(4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDINE##STR42## EXAMPLES 42 TO 48

By performing the process as in Examples 24 to 30 but starting withN-(4,6-dimethyl-2-pyridyl)-3-thienylacetamide, the following arerespectively obtained:

EXAMPLE 42 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLTHIOACETAMIDE

Melting point: 69° C.

EXAMPLE 43 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDE HYDRAZONE##STR43## EXAMPLE 44 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDOXIME

Melting point: 131° C. ##STR44##

EXAMPLE 45 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYL-O-METHYLACETAMIDOXIME##STR45## EXAMPLE 46N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYL-O-BENZYLACETAMIDOXIME ##STR46##EXAMPLE 47 N-(4,6-DIMETHYL-2-PYRIDYL)-N'-METHYL-3-THIENYLACETAMIDINE##STR47## EXAMPLE 48 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLACETAMIDINE##STR48## EXAMPLE 49N-(4,6-DIMETHYL-5-NITRO-2-PYRIDYL)-2-PYRAZINECARBOXAMIDE

By performing the process as in Example 22 but starting with2-amino-5-nitro-4,6-dimethyl-pyridine, the title product is obtained.

Melting point: 158° C.

EXAMPLE 50 N-(4,6-DIMETHYL-2-PYRIDYL)-PHTHALIMIDOACETAMIDE ##STR49##

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 2-phthalimidoacetic acid, the title product isobtained.

Melting point: 212°-213° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (solvent CDCl₃)

CH₂ : singlet; 2H : 4,54 ppm

EXAMPLE 51 N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDINECARBOXAMIDE ##STR50##

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 4-pyridinecarboxylic acid, the title product isobtained.

Melting point: 142° C.

EXAMPLE 52 N-(4,6-DIMETHYL-2-PYRIDYL)-(2-METHYLTHIO-3-PYRIDYL)ACETAMIDE

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 2-methylthio-3-pyridinecarboxylic acid, thetitle product is obtained.

Melting point: 164° C.

EXAMPLE 53 N-(4,6-DIMETHYL-2-PYRIDYL)-(2-HYDROXY-3-PYRIDYL)CARBOXAMIDE

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 2-hydroxy-3-pyridinecarboxylic acid, the titleproduct is obtained.

Melting point: 245° C.

EXAMPLE 54 N-(4,6-DIMETHYL-2-PYRIDYL)-(2-CHLORO-3-PYRIDYL)CARBOXAMIDE

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 2-chloro-3-pyridinecarboxylic acid, the titleproduct is obtained.

Melting point: 91° C.

EXAMPLE 55 N-(4,6-DIMETHYL-2-PYRIDYL)-2-CHLOROBENZOb!THIENYL-3-CARBOXAMIDE

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 2-chlorobenzo b!thienyl-3-carboxylic acid, thetitle product is obtained.

EXAMPLES 56 to 62

By performing the process as in Examples 24 to 30 but starting withN-(4,6-dimethyl-2-pyridyl)-2-chlorobenzo b!thienyl-3-acetamide (compoundof Example 19), the following are respectively obtained:

EXAMPLE 56 N-(4,6-DIMETHYL-2-PYRIDYL)-2-CHLOROBENZOb!THIENYL-3-THIOACETAMIDE EXAMPLE 57N-(4,6-DIMETHYL-2-PYRIDYL)-2-CHLOROBENZO b!THIENYL-3-ACETAMIDE HYDRAZONEEXAMPLE 58 N-(4,6-DIMETHYL-2-PYRIDYL)-2-CHLOROBENZOb!THIENYL-3-ACETAMIDOXIME EXAMPLE 59N-(4,6-DIMETHYL-2-PYRIDYL)-O-METHYL-2-CHLOROBENZOb!-THIENYL-3-ACETAMIDOXIME EXAMPLE 60 N-(4,6-DIMETHYL-2-PYRIDYL)-O-BENZYL-2-CHLOROBENZO b!-THIENYL-3-ACETAMIDOXIME EXAMPLE 61N-(4,6-DIMETHYL-2-PYRIDYL)-N'-METHYL-2-CHLOROBENZOb!-THIENYL-3-ACETAMIDINE EXAMPLE 62N-(4,6-DIMETHYL-2-PYRIDYL)-2-CHLOROBENZO b!THIENYL-3-ACETAMIDINE EXAMPLE63 N-(4,6-DIMETHYL-2-PYRIDYL)-4-OXO 4H!BENZOPYRAN-2-YL-ACETAMIDE

By performing the process as in Example 1 but replacing the2-(thien-2-yl)acetic acid by 4-oxo 4H!benzopyran-2-ylacetic acid, thetitle product is obtained.

EXAMPLES 64 TO 70

By performing the process as in Examples 24 to 30 but starting withN-(4,6-dimethyl-2-pyridyl)-4-oxo 4H!benzopyran-2-ylcarboxamide (compoundof Example 20), the following are respectively obtained:

EXAMPLE 64 N-(4,6-DIMETHYL-2-PYRIDYL)-4-OXO4H!BENZOPYRAN-2-YLTHIOCARBOXAMIDE EXAMPLE 65N-(4,6-DIMETHYL-2-PYRIDYL)-4-OXO 4H!BENZOPYRAN-2-YLCARBOXAMIDE HYDRAZONEEXAMPLE 66 N-(4,6-DIMETHYL-2-PYRIDYL)-4-OXO4H!BENZOPYRAN-2-YLCARBAMIDOXIME EXAMPLE 67N-(4,6-DIMETHYL-2-PYRIDYL)-O-METHYL-4-OXO4H!BENZOPYRAN-2-YLCARBAMIDOXIME EXAMPLE 68N-(4,6-DIMETHYL-2-PYRIDYL)-O-BENZYL-4-OXO4H!BENZOPYRAN-2-YLCARBAMIDOXIME EXAMPLE 69N-(4,6-DIMETHYL-2-PYRIDYL-N'-METHYL-4-OXO4H!BENZOPYRAN-2-YLCARBOXAMIDINE EXAMPLE 70N-(4,6-DIMETHYL-2-PYRIDYL)-4-OXO 4H!BENZOPYRAN-2-YL-CARBOXAMIDINEEXAMPLES 71 TO 77

By performing the process as in Examples 24 to 30 but starting withN-(4,6-dimethyl-2-pyridyl)-4-pyridinecarboxamide (compound of Example51), the following are respectively obtained:

EXAMPLE 71 N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDINETHIOCARBOXAMIDE EXAMPLE72 N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDINECARBOXAMIDE HYDRAZONE EXAMPLE 73N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDINECARBAMIDOXIME EXAMPLE 74N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDYL-O-METHYLCARBAMIDOXIME EXAMPLE 75N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDYL-O-BENZYLCARBAMIDOXIME EXAMPLE 76N-(4,6-DIMETHYL-2-PYRIDYL)-N'-METHYL-4-PYRIDYLCARBOXAMIDINE EXAMPLE 77N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDYLCARBOXAMIDINE EXAMPLE 78N-(4,6-DIMETHYL-2-PYRIDYL)-4-PYRIDYLACETAMIDE

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 4-pyridineacetic acid, the title product isobtained.

EXAMPLE 79 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLPROPIONAMIDE

By performing the process as in Example 1 but starting with3-thienylpropionic acid, the title product is obtained.

EXAMPLE 80 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLBUTANAMIDE

By performing the process as in Example 1 but starting with3-thienylbutanoic acid, the title product is obtained.

EXAMPLE 81 N-(4,6-DIMETHYL-2-PYRIDYL)-3-THIENYLPROPENAMIDE

By performing the process as in Example 1 but starting with3-thienylpropenoic acid, the title product is obtained.

EXAMPLE 82 N-(4,6-DIMETHYL-2-PYRIDYL)BENZOPYRAN-3-YLCARBOXAMIDE

By performing the process as in Example 1 but starting withbenzopyran-3-ylcarboxylic acid, the title product is obtained.

EXAMPLE 83 N-(4,6-DIMETHYL-2-PYRIDYL)BENZOPYRAN-3-YLACETAMIDE

By performing the process as in Example 1, but starting withbenzopyran-3-ylacetic acid, the title product is obtained.

EXAMPLE 84 N-(4,6-DIMETHYL-2-PYRIDYL)-3-CHROMANYLCARBOXAMIDE ##STR51##

By performing the process as in Example 1 but starting withchroman-3-ylcarboxylic acid, the title product is obtained.

EXAMPLE 85 N-(4,6-DIMETHYL-2-PYRIDYL)-3-CHROMANYLACETAMIDE

By performing the process as in Example 1 but starting withchroman-3-ylacetic acid, the title product is obtained.

EXAMPLE 86 N-(4,6-DIMETHYL-2-PYRIDYL)-5-METHYL-2-PYRAZINECARBOXAMIDE

By performing the process as in Example 2 but replacing the2-thienylacetic acid by 5-methyl-2-pyrazinecarboxylic acid and the2-ethylamino-4,6-dimethylpyridine by 2-amino-4,6-dimethylpyridine, thetitle product is obtained in the form of a white powder which isrecrystallized from an ethyl acetate/chloroform mixture (7/3).

Melting point: 169° C.

EXAMPLES 87 TO 93

By performing the process as in Examples 24 to 30 but starting withN-(4,6-dimethyl-2-pyridyl)-5-methyl-2-pyrazinecarboxamide (compound ofExample 86), the following are respectively obtained:

EXAMPLE 87 N-(4,6-DIMETHYL-2-PYRIDYL)-5-METHYL-2-PYRAZINETHIOCARBOXAMIDE

Recrystallization: isopropyl ether/petroleum ether 9/1

Yield: 43%

Melting point: 129° C.

Spectral characteristics:

Infrared

3260 cm⁻¹ : ν NH

¹ H Nuclear Magnetic Resonance (CDCl₃)

CH₃ (position 5 of the pyrazine): singlet, 3H, 2.67 ppm

EXAMPLE 88 N-(4,6-DIMETHYL-2-PYRIDYL)-5-METHYL-2-PYRAZINECARBOXAMIDEHYDRAZONE EXAMPLE 89N-(4,6-DIMETHYL-2-PYRIDYL)-5-METHYL-2-PYRAZINECARBOXAMIDOXIME

Melting point: 173° C.

EXAMPLE 90N-(4,6-DIMETHYL-2-PYRIDYL)-5-METHYL-2-PYRAZINYL-O-METHYLCARBOXAMIDOXIME

Melting point: 137° C.

EXAMPLE 91N-(4,6-DIMETHYL-2-PYRIDYL)-5-METHYL-2-PYRAZINYL-O-BENZYLCARBOXAMIDOXIMEEXAMPLE 92N-(4,6-DIMETHYL-2-PYRIDYL)-N'-METHYL-5-METHYL-2-PYRAZINCARBOXAMIDINEEXAMPLE 93 N-(4,6-DIMETHYL-2-PYRIDYL)-5-METHYL-2-PYRAZINECARBOXAMIDINEEXAMPLE 94 N-(4,6-DIMETHYL-2-PYRIDYL)-3-(1-PYRROLIDINYL)-2-BUTENAMIDE##STR52##

4.52 g (23.6 mmol) of N-(4,6-dimethyl-2-pyridyl)-2-acetoacetamide,obtained by condensation of a pyridine and ethyl acetoacetate, 2.02 g(28.6 mmol) of pyrrolidine and 55 ml of benzene are introduced into a250 ml round-bottomed flask on which is fitted a Dean-Stark apparatus.The mixture is heated at reflux for one hour. The solvent is evaporatedoff. The crystals are washed with isopropyl ether. The title product, ofecru color, is collected.

Melting point: 132° C.

EXAMPLE 95 N-(4,6-DIMETHYL-2-PYRIDYL)-3-(1-PYRROLIDINYL)BUTANAMIDE##STR53##

1.37 g (5.3 mmol) of the compound obtained in Example 94 and 60 ml ofmethanol are introduced into a 250 ml round-bottomed flask. 1 g (27mmol) of sodium borohydride is added slowly thereto. The mixture is leftstirring at room temperature for 1 h 30. The solvent is evaporated offand the residue is taken up in water. This mixture is extracted withdichloromethane. The organic extracts are evaporated and the crudeproduct is purified by passage through a column of silica gel, elutingwith a dichloromethane/ethanol mixture (90/10). The product obtained isviscous and crystallizes slowly.

EXAMPLE 96N-(4,6-DIMETHYL-2-PYRIDYL)-(3-ETHOXYCARBONYL-5-METHYL-4-ISOXAZOLYL)CARBOXAMIDE##STR54##

A solution of 3.5 g (13.51 mmol) of the compound obtained in Example 94in 30 ml of dichloromethane is cooled to 0° C. 2.62 g of ethylchlorooximidoacetate are added thereto in a single portion. The stirringis continued at 0° C. for 3 hours. The reaction medium is poured intowater and the mixture is extracted with dichloromethane. The organicphase is washed with 5% hydrochloric acid solution and then withsaturated sodium bicarbonate solution. The solution is dried and thesolvent is evaporated off. The product is purified by passing through acolumn of silica gel, eluting with isopropyl ether. The product obtainedis in the form of white crystals.

Melting point: 108° C.

Spectral characteristics:

¹ H Nuclear Magnetic Resonance (CDCl₃):

CH₂ : doublet 2H: 4.60 ppm

EXAMPLE 97N-(4,6-DIMETHYL-2-PYRIDYL)-(3-CARBOXY-5-METHYL-4-ISOXAZOLYL)CARBOXAMIDE##STR55##

A solution of 0.27 g (11.5 mmol) of lithium hydroxide in 3 ml of waterand 15 ml of methanol is cooled to -15° C. 1.5 g (5.19 mmol) of theproduct obtained in Example 96 are added slowly thereto with stirring.The stirring is continued for one hour. The mixture is acidified withdilute hydrochloric acid solution. The temperature is allowed to rise to0° C. and stirring is continued for 30 min. The mixture is filtered andthe title product is collected in the form of a white powder which iswashed with t-butyl methyl ether.

Melting point: 183° C.

EXAMPLE 98 N-(4,6-DIMETHYL-2-PYRIDYL)-3-PIPERIDYL-2-BUTENAMIDE

By performing the process as in Example 94 but replacing the pyrrolidineby piperidine, the title product is obtained.

EXAMPLE 99 N-(4,6-DIMETHYL-2-PYRIDYL)-3-PYRROLIN-1-YL-2-BUTENAMIDE##STR56##

By performing the process as in Example 94 but replacing the pyrrolidineby pyrroline, the title product is obtained.

EXAMPLE 100 N-(4,6-DIMETHYL-2-PYRIDYL)-(1-METHYL-2-PYRROLYL)ACETAMIDE##STR57##

By performing the process as in Example 1 but replacing the2-thienylacetic acid by 1-methyl-2-pyrrolylacetic acid, the titleproduct is obtained.

Melting point: 85° C.

PHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION EXAMPLE ASTUDY OF THE ACUTE TOXICITY

The acute toxicity was evaluated after oral administration to batches of8 mice (26±2 grams) of a dose of 650 mg.kg⁻¹. The animals were observedat regular intervals throughout the first day and daily during the 2weeks following the treatment. The compounds of the invention appear tobe totally nontoxic. No death is observed after administration of a doseof 650 mg.kg⁻¹. No disorders are observed after administration of thisdose.

EXAMPLE B STUDY OF THE ANTI-INFLAMMATORY ACTIVITY

The method used is that of plantar edema using carrageenan. Theprocedure used is as follows: 1% carrageenan in 0.2 ml of 9% salinesolution is administered into the sole of the right foot ofSprague-Dawley rats weighing 250 g on average. The volume of the paw ismeasured by plethysmography after one hour and after two hours.

The compounds of the invention are administered in a 10 mg/kg oral dose30 minutes before the administration of carrageenan. A saline solutionis injected into the sole of the left foot, which serves as a control.

The compounds of the invention make it possible to reduce the increasein volume of the right foot relative to that of the left foot (Table 1).

                  TABLE 1                                                         ______________________________________                                                            Percentage of inhibition                                  Compounds             1 h       2 h                                           ______________________________________                                         ##STR58##            63%       70%                                            ##STR59##            55%       64%                                           Indomethacin (10 mg/kg)                                                                             24%       64%                                           ______________________________________                                    

The compounds of the invention very strongly inhibit the inflammationinduced by carrageenan from 1 h and are more active than indomethacin,which is taken as a reference and administered under the sameconditions.

EXAMPLE C STUDY OF THE DIURETIC ACTIVITY

Groups of 3 fasted rats are used. Each group receives 25 ml/kg orally(p.o) of distilled water administered with the products of the inventionat a dose of 3 mg/kg.

The urinary volume is measured during the 6 hours following theadministration.

Thus, for example, the compound of Example 25 allows the urinary volumeto be increased by a factor 2.8 relative to an untreated rat.

When administered at a dose of 5 mg/kg p.o., furosemide, taken as areference, allows the urinary volume to be increased by a factor of 3.

The diuretic power of the products of the invention is thus comparableto that of furosemide.

EXAMPLE D DEMONSTRATION OF THE ACTIVITY AGAINST ACUTE CUTANEOUSINFLAMMATION (TOPICAL)

Phorbol ester (phorbol 12-myristate 13-acetate) (5 μg) is appliedtopically to the front and back surfaces of the right ear of the mouse30 minutes after application of the vehicle (95% ethanol) or of theagent (1 mg). The difference in thickness between the right ear and theleft ear (edema) is measured 6 hours after application.

The percentage of inhibition of cutaneous inflammation relative to agroup of animals treated topically with 95% ethanol is calculated. Thecompound of Example 1, at a rate of 1 mg/ear, allows a 63% reduction ofthe inflammation. Indomethacin, taken as a reference, at a dose of 2.5mg/ear, allows a 67% reduction of inflammation.

EXAMPLE E CURATIVE ACTIVITY AND ACTIVITY AFTER REPEATED TOPICALAPPLICATION IN THE ESTABLISHED MODEL OF CHRONIC INFLAMMATION OF THE EARSUBJECTED TO A REPEATED APPLICATION OF PHORBOL ESTER (PMA) FOR 15 DAYS("PERTINENT" MODEL OF PSORIASIS)

Phorbol ester (1 μg) is applied topically to the front and back surfacesof the right ear of the mouse on days 0, 2, 4, 7, 9, 11 and 14. Thevehicle or the agent is applied topically twice daily, on days 7, 8, 9,10, 11, 12, 13 and 14, and once on the 15th day. On days 7, 9, 11 and 14the vehicle or the agent is applied 30 minutes before and after thephorbol ester.

Two parameters are measured

1. Difference in thickness between the right and left ears every day andon days 0, 2, 4, 7, 9, 11 and 14, 6 hours after repeated application ofthe phorbol ester.

After repeated application of phorbol ester and after 15 days, thethickness reflects not only the presence of an edema and of aninfiltration of lymphocyte and monocyte-macrophage neutrophil type cellsin the skin tissue (inflammation) but also of an increase in thethickness of the epidermis (epidermal hyperplasia secondary to aproliferation of keratinocytes). These two processes constitute thephysiopathological bases of psoriasis.

2. Difference in weight ("ear punches") between the right and left earson the 10th day. In this chronic model, 15 days after repeatedapplication of phorbol ester, the standard anti-inflammatory agentsinhibiting cyclooxygenase (indomethacin and piroxicam) are topicallyinactive but, however, medicinal products currently used in thetreatment of psoriasis (cyclosporin A and corticoids) are topicallyactive. Thus, cyclosporin A and hydrocortisone were used as referencesubstances. A group receiving ethanol serves as a control.

The products of the invention, in topical, curative and repeated use,inhibit, between the 8th and 10th days, the chronic inflammation of theright ear (measured, on the one hand, by the difference in thicknessbetween the right ear and the left ear, and, on the other hand, by thedifference in weight between the two ears after sacrificing the animalon the 15th day) induced by a repeated application of phorbol ester inmice.

For example, at a dose of 0.5 mg/ear, the compound of Example 17 allowsa 60% reduction of the difference in thickness between the two ears andallows a 38% reduction of the weight difference.

EXAMPLE F STUDY OF AN ACTIVITY OF ANTI-ARTHRITIC TYPE IN RATS

Groups of 5 male or female Lewis rats weighing from 130 to 150 g areused. A suspension of 0.3 mg of killed Mycobacterium tuberculosis in 0.1cm³ of mineral oil (complete Freund adjuvant, CFA) is administered intothe subplantar region of the right hind foot on day 1. The volumes ofthe hind feet are measured by water displacement on days 0, 1, 5, 14 and18. The rats are weighed on days 0 and 18. The test products aresuspended in carboxymethylcellulose and administered orally for 5consecutive days, on days 1 to 5. In parallel, a control group is usedin order to eliminate artefacts resulting from the handling of theanimals. A group treated with a reference product (hydrocortisone)allows the test to be validated.

On day 18, the compound of Example 1 thus allows a 47% reduction in thevolume of the right hind foot.

The products of the invention possess a powerful inhibitory action inthis model, which places them as very interesting candidates for thetreatment of arthritis.

PHARMACEUTICAL COMPOSITIONS EXAMPLE A TABLETS FOR THE TREATMENT OFINFLAMMATORY DISEASES AND RENAL DISEASES

Compounds containing a 10 mg dose ofN-(4,6-dimethyl-2-pyridyl)-3-thienylacetamide

    ______________________________________                                        Preparation formula for 1000 tablets                                          ______________________________________                                        N-(4,6-Dimethyl-2-pyridyl)-3-thienylacetamide                                                            10 g                                               Wheat starch               35 g                                               Corn starch                65 g                                               Lactose                    65 g                                               Magnesium stearate         2 g                                                Silica                     1 g                                                Hydroxypropylcellulose     2 g                                                ______________________________________                                    

EXAMPLE B OINTMENT INTENDED FOR THE TREATMENT OF PSORIASIS ANDCONTAINING A 1% DOSE OF N-4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE

Preparation formula for 100 kg

N-(4,6-Dimethyl-2-pyridyl)-2-thienylacetamide 1000 g

Excipient in sufficient quantity for 100 kg

(Cetyl alcohol, stearyl alcohol, isopropyl alcohol; lanolin,polyethylene glycol monostearate, distilled common laurel cherry water).

We claim:
 1. A compound selected from those of formula (I): ##STR60## inwhich m is equal to 0 or 1,the symbol ##STR61## representing thepyridine ring when m is equal to 0 and pyridine N-oxide when m is equalto 1,the pyridine system ##STR62## being connected to the group##STR63## which bears it either in the 2-position or in the 3-positionof the pyridine ring; R₁ and R₂, which may be identical or different,are chosen, independently of each other, from hydrogen, amino,alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, nitro, and halogen, R₃and R₄, which may be identical or different, are chosen, independentlyof each other, from amino, alkylamino, dialkylamino, alkyl, hydroxy,alkoxy, nitro, and halogen, R represents hydrogen or alkyl, A representsa single bond; and in this case Het represents a group chosen frompyrazine and substituted pyrazine, or alternatively A representsalkylene which is unsubstituted or substituted with one or more alkyl,or alkenylene which is unsubstituted or substituted with one or morealkyl; and in this case Het also represents a group chosen from pyrazineand substituted pyrazine, X represents oxygen, imino, or iminosubstituted with a group chosen from alkyl, alkoxy, hydroxy, amino,arylalkyloxy, and aryloxy, an enantiomer and a diastereoisomer thereofand an addition salt thereof with a pharmaceutically-acceptable acid orbase, it being understood that, except where otherwise mentioned:theterm "substituted" relating to the pyrazine system means that it issubstituted with one or more groups chosen from alkyl, alkoxy,trifluoromethyl, hydroxy, halogen, thio, and alkylthio, the terms"alkyl", "alkoxy", and "alkylene" denote linear or branched groupscontaining 1 to 6 carbon atoms, inclusive, the term "aryl" denotesphenyl or naphthyl, the term "alkenylene" denotes a linear or branchedunsaturated chain containing 2 to 6 carbon atoms, inclusive.
 2. Acompound of claim 1, which is selected from those compounds having theformula (IA): ##STR64## in which m represents 0 or 1, and Het representspyrazine or pyrazine substituted with alkyl and A is a single bond,and Xrepresents oxygen, imino or imino substitued with a hydroxyl, a methoxy,a methyl, amino or benzyloxy, an enantiomer and a diastereoisomerthereof and an addition salt thereof with a pharmaceutically-acceptableacid.
 3. A compound of claim 1, which is selected fromN-(4,6-dimethyl-2-pyridyl)-2-pyrazinecarbamidoxime, of formula:##STR65## the N-oxide thereof and an addition salt thereof, with apharmaceutically-acceptable acid.
 4. A compound of claim 1, which isselected fromN-(4,6-dimethyl-2-pyridyl)-O-methyl-2-pyrazinecarbamidoxime, of formula:##STR66## the N-oxide thereof, an enantiomer thereof, and an additionsalt thereof with a pharmaceutically-acceptable acid.
 5. A compound ofclaim 1, which is selected fromN-(4,6-dimethyl-2-pyridyl)-5-methyl-2-pyrazinethiocarboxamide, theN-oxide thereof, and an addition salt thereof with apharmaceutically-acceptable acid.
 6. A compound of claim 1, which isselected from N-(4,6-dimethyl-2-pyridyl)-2-pyrazinecarboxamidine, theN-oxide thereof, and an addition salt thereof with apharmaceutically-acceptable acid.
 7. A compound of claim 1, which isselected fromN-(4,6-dimethyl-2-pyridyl)-N'-methyl-2-pyrazinecarboxamidine, theN-oxide thereof, and an addition salt thereof with apharmaceutically-acceptable acid.
 8. A pharmaceutical composition usefulfor treating inflammatory disorders containing as active principle atleast one compound selected from those of formula (I): ##STR67## inwhich m is equal to 0 or 1,the symbol ##STR68## representing thepyridine ring when m is equal to 0 and pyridine N-oxide when m is equalto 1, the pyridine system ##STR69## being connected to the group##STR70## which bears it either in the 2-position or in the 3-positionof the pyridine ring; R₁ and R₂, which may be identical or different,are chosen, independently of each other, from hydrogen, amino,alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, nitro, and halogen, R₃and R₄, which may be identical or different, are chosen, independentlyof each other, from amino, alkylamino, dialkylamino, alkyl, hydroxy,alkoxy, nitro, and halogen, R represents hydrogen or alkyl, A representsa single bond; and in this case Het represents a group chosen frompyrazine and substituted pyrazine, or alternatively A representsalkylene which is unsubstituted or substituted with one or more alkyl,or alkenylene which is unsubstituted or substituted with one or morealkyl; and in this case Het also represents a group chosen from pyrazineand substituted pyrazine, X represents oxygen, imino, or iminosubstituted with a group chosen from alkyl, alkoxy, hydroxy, amino,arylalkyloxy, and aryloxy, an enantiomer and a diastereoisomer thereofand an addition salt thereof with a pharmaceutically-acceptable acid orbase, it being understood that the term "substituted" relating to thepyrazine system means that it is substituted with one or more groupschosen from alkyl, alkoxy, trifluoromethyl, hydroxy, halogen, thio, andalkylthio,the terms "alkyl", "alkoxy", and "alkylene" denote linear orbranched groups containing 1 to 6 carbon atoms, inclusive, the term"aryl" denotes phenyl or naphthyl, the term "alkenylene" denotes alinear or branched unsaturated chain containing 2 to 6 carbon atoms,inclusive, in combination with one or more pharmaceutically-acceptableexcipients or vehicles.
 9. A method of treating a mammal afflicted withan inflammatory disorder comprising the step of administering to thesaid mammal an amount of a compound selected from those of formula (I):##STR71## in which m is equal to 0 or 1,the symbol ##STR72##representing the pyridine ring when m is equal to 0 and pyridine N-oxidewhen m is equal to 1, the pyridine system ##STR73## being connected tothe group ##STR74## which bears it either in the 2-position or in the3-position of the pyridine ring; R₁ and R₂, which may be identical ordifferent, are chosen, independently of each other, from hydrogen,amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, nitro, andhalogen, R₃ and R₄, which may be identical or different, are chosen,independently of each other, from amino, alkylamino, dialkylamino,alkyl, hydroxy, alkoxy, nitro, and halogen, R represents hydrogen oralkyl, A represents a single bond; and in this case Het represents agroup chosen from pyrazine and substituted pyrazine, or alternatively Arepresents alkylene which is unsubstituted or substituted with one ormore alkyl, or alkenylene which is unsubstituted or substituted with oneor more alkyl; and in this case Het also represents a group chosen frompyrazine and substituted pyrazine, X represents oxygen, sulfur, imino,or imino substituted with a group chosen from alkyl, alkoxy, hydroxy,amino, arylalkyloxy, and aryloxy, an enantiomer and a diastereoisomerthereof and an addition salt thereof with a pharmaceutically-acceptableacid or base, it being understood that the term "substituted" relatingto the pyrazine system means that it is substituted with one or moregroups chosen from alkyl, alkoxy, trifluoromethyl, hydroxy, halogen,thio, and alkylthio,the terms "alkyl", "alkoxy", and "alkylene" denotelinear or branched groups containing 1 to 6 carbon atoms, inclusive, theterm "aryl" denotes phenyl or naphthyl, the term "alkenylene" denotes alinear or branched unsaturated chain containing 2 to 6 carbon atoms,inclusive, which is effective for alleviating the said disorder.
 10. Apharmaceutical composition according to claim 8 wherein the compound hasthe formula (IA): ##STR75## in which m represents 0 or 1, and Hetrepresents pyrazine or alkylpyrazine and A represents a single bond,andX represents oxygen, imino, or imino substituted with a hydroxyl, amethoxy, a methyl, amino, or benzyloxy, an enantiomer and adiastereoisomer thereof and an addition salt thereof with apharmaceutically-acceptable acid.
 11. A pharmaceutical compositionaccording to claim 8 wherein the compound is selected from the groupconsisting of N-(4,6-dimethyl-2-pyridyl)-2-pyrazinecarboxamidoxime orthe O-methyl derivative thereof, or an N-oxide of any of the foregoing,and the addition salts thereof with a pharmaceutically-acceptable acid.12. A pharmaceutical composition according to claim 8 wherein thecompound is selected from the group consisting ofN-(4,6-dimethyl-2-pyridyl)-5-methyl-2-pyrazinethiocarboxamide,N-(4,6-dimethyl-2-pyridyl)-2-pyrazinecarboxamidine or the N'-methylderivative thereof, or an N-oxide of any of the foregoing, and theaddition salts thereof with a pharmaceutically-acceptable acid.
 13. Amethod of claim 9, wherein the compound has the formula (IA): ##STR76##in which m represents 0 or 1, and Het represents pyrazine oralkylpyrazine and A represents a single bond,and X represents oxygen,sulfur, imino, or imino substituted with a hydroxyl, a methoxy, amethyl, amino, or benzyloxy, an enantiomer and a diastereoisomer thereofand an addition salt thereof with a pharmaceutically-acceptable acid.14. A method of claim 9, wherein the compound is selected from the groupconsisting of N-(4,6-dimethyl-2-pyridyl)-2-pyrazine carboxamidoxime orthe O-methyl derivative thereof, or an N-oxide of any of the foregoing,and the addition salts thereof with a pharmaceutically-acceptable acid.15. A method of claim 9, wherein the compound is selected from the groupconsisting ofN-(4,6-dimethyl-2-pyridyl)-5-methyl-2-pyrazinethiocarboxamide,N-(4,6-dimethyl-2-pyridyl)-2-pyrazine-carboxamidine or the N'-methylderivative thereof, or an N-oxide of any of the foregoing, and theaddition salts thereof with a pharmaceutically-acceptable acid.